title: Heme oxygenase-1 protects interstitial cells of Cajal from oxidative stress and reverses diabetic gastroparesis.
abstract: OBJECTIVE
  Diabetic gastroparesis (delayed gastric emptying) is a well-recognized complication of diabetes that causes considerable morbidity and makes glucose control difficult. Interstitial cells of Cajal, which express the receptor tyrosine kinase Kit, are required for normal gastric emptying. We proposed that Kit expression is lost during diabetic gastroparesis due to increased levels of oxidative stress caused by low levels of heme oxygenase-1 (HO-1), an important cytoprotective molecule against oxidative injury.
  
  
  METHODS
  Gastric emptying was measured in nonobese diabetic mice and correlated with levels of HO-1 expression and activity. Endogenous HO-1 activity was increased by administration of hemin and inhibited by chromium mesoporphyrin.
  
  
  RESULTS
  In early stages of diabetes, HO-1 was up-regulated in gastric macrophages and remained up-regulated in all mice that were resistant to development of delayed gastric emptying. In contrast, HO-1 did not remain up-regulated in all the mice that developed delayed gastric emptying; expression of Kit and neuronal nitric oxide synthase decreased markedly in these mice. Loss of HO-1 up-regulation increased levels of reactive oxygen species. Induction of HO-1 by hemin decreased reactive oxygen species, rapidly restored Kit and neuronal nitric oxide synthase expression, and completely normalized gastric emptying in all mice. Inhibition of HO-1 activity in mice with normal gastric emptying caused a loss of Kit expression and development of diabetic gastroparesis.
  
  
  CONCLUSIONS
  Induction of the HO-1 pathway prevents and reverses cellular changes that lead to development of gastrointestinal complications of diabetes. Reagents that induce this pathway might therefore be developed as therapeutics.
authors.affiliation: Enteric NeuroScience Program, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Kyoung Moo
authors.initials: KM
authors.lastname: Choi
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Gibbons
authors.forename: Tien V
authors.initials: TV
authors.lastname: Nguyen
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Stoltz
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Lurken
authors.forename: Tamas
authors.initials: T
authors.lastname: Ordog
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Szurszewski
authors.forename: Gianrico
authors.initials: G
authors.lastname: Farrugia
mesh_terms: D000818:Animals; D015153:Blotting, Western; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D005746:Gastric Emptying; D005753:Gastric Mucosa / Q000378:metabolism* / Q000473:pathology; D018589:Gastroparesis / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D051547:Heme Oxygenase-1 / Q000096:biosynthesis*; D007150:Immunohistochemistry; D051379:Mice; D016688:Mice, Inbred NOD; D018384:Oxidative Stress / Q000502:physiology*
chemical_list: D051547:Heme Oxygenase-1